Obesity and its metabolic sequelae already underlie hundreds of billions of dollars in annual health care expenditures, and the incidence of obesity is projected to rise to 40% within the next fifteen years. The need to understand the mechanisms controlling energy balance and metabolism thus continues to grow ever more pressing, since this knowledge will be crucial for defining pathogenic mechanisms and for the development of novel therapies. Leptin, an adipocyte-derived hormone secreted in proportion to adipose energy stores, acts via the long isoform of its receptor (LepRb) in the central nervous system to control behavior (e.g., feeding) and physiology (e.g., glucose homeostasis) relevant to energy balance. The central role played by leptin in the control of energy homeostasis suggests the importance of understanding the mechanisms by which leptin mediates its effects. Leptin-responsive (LepRb-expressing) neurons lie in a number of brain regions crucial for the control of metabolic function, including mediobasal hypothalamic (MBH) nuclei (e.g., arcuate nucleus (ARC)) and the brainstem. While MBH leptin action is important and has received considerable attention in recent years, MBH leptin signaling can only account for a fraction of leptin action. The brainstem contains a number of distinct populations of LepRb neurons; the periaqueductal grey (PAG) and lateral parabrachial (lPBN) nuclei contain the largest groups of brainstem LepRb neurons (comparable to LepRb populations in major hypothalamic nuclei). While both of these nuclei contribute to the control of satiety and autonomic function, the roles for LepRb neurons in these regions remain unknown. We found that many PAG/lPBN LepRb neurons contain the neuropeptide, cholecystokinin (CCK), and that the distribution of these LepRbCCK neurons is restricted to the brainstem. Furthermore, our preliminary data reveal roles for these neurons in the control of food intake, body weight, and the glucoprivic response. In this proposal, we will employ a panel of molecular genetic tools to define the regulation and connectivity of brainstem LepRb neurons. Furthermore, we will manipulate the activity of these neurons, as well as their responsiveness to leptin, in order to define their neural and physiologic functions. These studies will provide important insights into novel mechanisms of leptin action in the central nervous system and into the control of energy and glucose homeostasis.